This application is a 371 of PCT/JP98/05842 filed Dec. 24, 1998.
1. Technical Field
The present invention relates to a chromatographic separation process and a chromatographic separator, and more particularly to a chromatographic separation process for separating a starting fluid material containing at least 3 components into at least 3 fractions in a plurality of steps with a chromatographic separator packed with an ion exchanger as at least part of chromatographic packing and a chromatographic separator not only effectively usable for the above-mentioned chromatographic separation process but also usable for a variety of other processes.
2. Background Art
There are various conventional methods of chromatographic separation of a starting fluid material containing at least 3 components into the respective components, representative examples of which include the following methods:
A method (1) is a batchwise one wherein analytical high-performance liquid chromatography is scaled up, and which is generally called preparatory chromatography.
A method (2) is one using either 2 simulated moving bed chromatographic separators for separation of only 2 components or using such a chromatographic separator twice as disclosed in Japanese Patent Laid-Open No. 124,895/1990. More specifically, a starting material is either first separated into a component A and a mixture of components B+C, followed by separation of the mixture of components B+C into the components B and C, or first separated into a mixture of components A+B and the component C, followed by separation of the mixture of components A+B into the components A and B. This is so because separation of only 2 components is possible with an ordinary simulated moving bed chromatographic separator. Thus, in order to actually separate 3 components from one another, either 2 simulated moving bed chromatographic separators must be prepared or one such separator must be used twice. In the latter case, a solution midway of separation (fraction of mixture) must be stored once, and then subjected to separation under varied conditions while using the same separator again.
A method (3) is one disclosed in Japanese Patent Laid-Open No. 227,804/1992, wherein one improved simulated moving bed chromatographic separator packed with one packing is used to efficiently and continuously separate a fluid mixture containing at least 3 components into fractions enriched with the respective components. Herein, the term xe2x80x9cenriched with componentsxe2x80x9d refers to solids-based concentration (enrichment) of components to be separated (components desired to be separated) in the respective fractions separated in the direction of fluid flow. Thus, the degree of enrichment is correlated with purity and recovery.
A method (4) is one disclosed in Japanese Patent Laid-Open No. 80,409/1989, wherein separation columns (packed column units having packing bed units) packed with a first packing having the following partition coefficients for components: component A less than component B less than component C are arrayed alternately and used together with separation columns packed with a second packing having the following partition coefficients for components: component A less than component C less than component B.
The methods (2), (3) and (4) are fundamentally those whereto application is made either of a basic simulated moving bed procedure comprising an operation of feeding a starting fluid material containing a plurality of components to be separated and desorbent (called xe2x80x9celuentxe2x80x9d in the case of liquid) at respective designated positions to an endless circulation system (loop) made up of a plurality of packing bed units packed with chromatographic packing (sorbent) and linked endlessly to flow the starting fluid material and the desorbent in one direction through the endless circulation system, and withdrawing fractions from zones enriched with respective components out of the endless circulation system while taking advantage of a phenomenon that a plurality of components to be separated are separated into respective zones enriched with the respective components due to a difference between the components in affinity for chromatographic packing, and an operation of intermittently displacing the starting fluid material and desorbent feed positions as well as the fraction withdrawal positions in the direction of fluid flow as if the chromatographic packing were apparently moved in the direction opposite to that of fluid flow, whereby two fractions enriched with the respective components are continuously obtained from the starting fluid material; or of an improved or altered procedure based on the basic simulated moving bed procedure (in the present invention, the xe2x80x9csimulated moving bed procedurexe2x80x9d is defined as encompassing such improved or altered ones as well).
Although the foregoing methods all belong to the same technology in respect of chromatographic separation of a starting fluid material containing at least 3 components into at least 3 fractions, they involve the following respective demerits when they are adopted in industrial-scale equipment for carrying out the separation technology.
The method (1) is poor in separation because it is batchwise, and is often unfit for industrial-scale separation involving treatment of a large amount of starting liquid material because the amount of eluent to be used must inevitably be large.
The method (2) requires either installing 2 simulated moving bed chromatographic separators or using the same separator twice. Where 2 simulated moving bed chromatographic separators are installed, the equipment cost is increased. Where the same separator is used twice, the same packing must inevitably be used because replacing chromatographic packing every time is troublesome in an aspect of operation. This involves a problem that all 3 components cannot efficiently be separated from one another in some cases because one kind of packing is used. For example, there arises a case where a component A is too well separated from a component B, but separation of the component B from a component C is so poor that it is difficult to heighten the component purities of all fractions.
The method (3) also sometimes fails in efficient and distinct separation of all 3 components because one kind of packing is used. For example, there arises a case where a component A is too well separated from a component B, but separation of the component B from a component C is so poor that it is difficult to heighten the component purities of all fractions.
The method (4) involves a difficulty in combining 2 kinds of suitable packings for a starting solution to be subjected to chromatographic separation.
Accordingly, in the foregoing methods (2), (3) and (4), the separability of components [relevant to the load (feed rate) of a starting fluid material], the purities and recoveries of components contained as objects of separation in recovered fractions, the amount of used desorbent relevant to concentration energy involved in concentrating recovered fractions (relevant to the desired component concentrations of the recovered fractions), etc. are influenced by packing(s) packed in packing bed units, while involving a problem that a countermeasure for an improvement in respect of one of those influences tends to produce other adverse effects.
Although it can be said that choice and use of the optimum packing capable of suitably adjusting the foregoing various influences will suffice in order to solve such a problem, choice of the optimum packing is not easy as a matter of fact. For example, when the resolution, by packing, of components contained in a starting fluid material is enhanced as much as possible in order to heighten the purities and recoveries of components as objects of recovery, intervals between a plurality of zones enriched with respective components are spread too broad in the endless circulation system, whereby the amount of desorbent to be used is increased (the amount of desorbent to be used for desorption of a strong-affinity component in particular is increased because of a large difference between components in affinity for packing), leading to a problem that the component concentrations of respective recovered fractions are lowered. On the other hand, using chromatographic packing poor in resolution for the purpose of decreasing the amount of desorbent to be used involves a problem that the purities and recoveries of components are lowered. Thus, the chances are rare that there exists any conventional packing suitable in respect of the resolution of a plurality of components to be separated, and creation of such a packing is not easy. Incidentally, the term xe2x80x9cresolution,xe2x80x9d which is a yardstick indicative of the extent of separation of 2 components, is defined as being equal to a value found by dividing the distance between the centers of two adjacent enriched zones (bands) 1 and 2 by an average band width (see xe2x80x9cHigh-Performance Liquid Chromatographyxe2x80x9d published by Tokyo Kagaku Dozin Co., Ltd. in 1976).
An object of the present invention, which has been made in view of the foregoing problems of the prior art technologies, is to provide a process for efficient chromatographic separation of components from a starting fluid material containing at least 3 components.
Another object of the present invention is to provide a chromatographic separator having a possibility of service in a wide variety of processes in addition to effective service to the above-mentioned process.
As a result of extensive investigations on the foregoing conventional is methods, the inventors of the present invention have solved the problems of the conventional chromatographic separation methods to complete the present invention. According to the present invention, for example, there can simultaneously be satisfied antinomic requirements that high purities and high recoveries of components as objects of separation be secured, and that the components be obtained while securing as high their concentrations as possible.
The chromatographic separation process of the present invention is characterized in that chromatographic separation is effected while changing at least part (based on ion exchange capacity) of the ionic form of part or the whole of an ion exchanger to an ionic form capable of increasing the resolution of components to be separated in each step in chromatographic separation for separating a starting fluid material containing at least 3 components into at least 3 fractions in at least 2 steps with a chromatographic separator packed with the ion exchanger as at least part of chromatographic packing (sorbent).
More specifically, the present invention provides a chromatographic separation process for separating a starting fluid material containing at least 3 components into at least 3 fractions in a plurality of steps with a chromatographic separator packed with an ion exchanger; characterized in that chromatographic separation is effected while changing at least part (based on ion exchange capacity) of the ionic form of part or the whole of the ion exchanger used as at least part of chromatographic packing (sorbent) to an ionic form fit for separation of components to be separated in each step. In the process of the present invention, use is preferably made of a chromatographic separator comprising a plurality of packing bed units packed with the ion exchanger as at least part of chromatographic packing, in which separator at least the position of feeding desorbent is intermittently displaced in the direction of fluid flow.
The present invention also provides a chromatographic separator comprising a system of a group of packing bed units packed with sorbent and linked in endless series to form a circulation flow path, in at least one position (shutoff/opening position) of which an interchange can be made between a state wherein internal fluid is endlessly circulated through the circulation flow path while allowing fluid to be fed into and withdrawn out of the system and a state wherein internal fluid flow is shut off while allowing fluid to be fed into and withdrawn out of the system; characterized by comprising a starting fluid feed means and a desorbent feed means connected to the circulation flow path between every adjacent packing bed units of the group of the packing bed units, 2-fluid withdrawal means connected to the circulation flow path between every adjacent packing bed units of the group of the packing bed units for respectively withdrawing 2 fluid fractions, and one or two fluid withdrawal means connected to the circulation flow path and disposed on the upstream side of said at least one position (shutoff/opening position) with no and/or one packing bed unit therebetween for withdrawing another fluid fraction.
The process of the present invention is not always limited to a case where only one kind of ion exchanger is used as the ion exchanger serving as at least part of chromatographic packing. As proposed by the instant applicant in Japanese Patent Application No. 9-257055 (i.e., 257,055/1997), the process of the present invention can also be applied to a case where the aforementioned resolution is adjusted by taking advantage of a coexistent state of at least 2 different packings selected from among those differing in the resolution of components to be separated which are contained in a starting fluid material, i.e., a case where said at least 2 different packings are used in a mixed state and/or a multi-layer stratified state and/or a coexistent state of said at least 2 different packings being used but, for example, only one packing among said at least 2 different packings being used in one or a plurality of packing bed units among a group of packing bed units endlessly linked In this case, the purpose of the present invention may be attained if only at least one packing among said at least 2 different packings is an ion exchanger. Ion exchange resins, zeolite, and the like can be used as the ion exchanger. Herein, the term xe2x80x9cdiffering in the resolutionxe2x80x9d refers to involving a difference of at least 0.1, preferably at least 0.2, between 2 packings in the resolution of 2 components to be separated from each other when that resolution is measured under actual separation conditions (temperature, flow velocity, etc.) for the 2 packings packed in respective test columns having the same shape, for example, at a standard packing bed height (e.g., 0.3- to 1-fold height of actual bed height of packed column unit). Where said at least 2 different packings are used in a coexistent state, examples of packing usable in combination with the ion exchanger include silica gel, activated carbon, and other natural or synthetic sorbents. The ratio, kinds, etc. of those packings can be chosen in accordance with the kinds of components to be separated, the purpose, etc. on the basis of various experimental results.
Since a smaller amount of a reagent for changing the ionic form of the ion exchanger is advantageous in aspects of expense, time, etc., it is preferred either to change the ionic form of the ion exchanger in an irreducible minimum amount or to change the ionic form of the ion exchanger at an irreducible minimum proportion (xe2x80x9cchanged ionic form/whole ionic form ratioxe2x80x9d based on the ion exchange capacity of the ion exchanger) even if the ionic form of the whole ion exchanger is changed. The term xe2x80x9cchanging the ionic formxe2x80x9d will hereinafter be defined as encompassing all such cases.
The process of the present invention may be carried out either according to a batchwise preparatory chromatographic separation procedure or according to a simulated moving bed chromatographic separation procedure. Accordingly, not only a wide variety of chromatographic separators such as a batchwise preparatory chromatographic separator, a basic simulated moving bed chromatographic separator and a simulated moving bed chromatographic separator for separation of 3 components as are used in the foregoing conventional methods but also a wide variety of improved or simplified chromatographic separators derived therefrom can be used as such in the process of the present invention. A batchwise preparatory chromatographic separator usually includes one bed, which is a packing bed packed with an ion exchanger in a column wherein the ionic form of the ion exchanger is changed in each step, but may alternatively be constructed in such a way that it includes, for example, two stratified beds differing in the ionic form of an ion exchanger in a column wherein a starting fluid material is flowed from the upstream end of the first bed and a first eluting (outflowing) fraction of mixture A+B from the first bed due to subsequent feed of desorbent is passed as such through the second bed to separately withdraw fractions A and B from the downstream end of the packed column (separation column) while withdrawing a fraction C from a position at the boundary between the first and second beds, whereby two steps with a change in the ionic form of the ion exchanger therebetween can be continuously taken in the batchwise separator. In the latter case, the separator may be constructed in such a way that a desorbent feed inlet is also provided at a position at the boundary between the first and second beds, or that a plurality of withdrawal outlets capable of switching the boundary between the first and second beds, for example, by changing the ionic form of the ion exchanger in the second bed, if necessary, through reverse utilization of the withdrawal outlets are provided favorably to enable the separator to cope with various operating conditions and various starting fluid materials. In a simulated moving bed chromatographic separator comprising a plurality of packing bed units (packed column units) packed with an ion exchanger as will be described later, a change in the ionic form of the ion exchanger in each step may be made either in such a manner that the ionic form of the ion exchanger in all the packing bed units is changed, or in such a manner that the ionic form of the ion exchanger in at least one packing bed unit is changed mostly to enable the purpose of the a present invention to be still attained. In this case, a packing other than ion exchanger may be used in combination with the ion exchanger as already described, and it is a matter of course that a packing other than ion exchanger may be used in all of at least one packing bed unit in so far as both are used in combination.
Reagents usable in changing the ionic form of, e.g., a cation exchanger as the ion exchanger include various acids; salts and hydroxides of alkali metals such as sodium and potassium as well as ammonium, and mixtures thereof, which can change the ionic form to a monovalent ion form; salts and hydroxides of alkaline earth metals such as calcium and magnesium, and mixtures thereof, which can change the ionic form to a bivalent ion form; and other reagents such as aluminum chloride, which can change the ionic form to a trivalent ion form or the like. A proper reagent may be chosen in connection with components to be separated.
For example, when a simulated moving bed chromatographic separator is used, a method wherein a solution of a salt, an acid or an alkali in an aqueous medium is flowed through at least one packing bed unit (packed column unit) is simple and convenient as the method of changing the ionic form of the ion exchanger. Alternatively, the ion exchanger such as an ion exchange resin may be transferred to a separate preparatory column and changed in the ionic form thereof in that column. From the standpoint of actual operation, a substantially neutral solution of a salt in an aqueous medium is preferably used rather than an acidic or alkaline aqueous solution.
For example, a gel type strongly acidic cation exchange resin is used for separation of saccharides. According to empirical laws, a monovalent ion form is so suitable for separation of monosaccharides, disaccharides, trisaccharides, etc. differing in molecular weight from one another that an aqueous solution of a salt such as sodium chloride is desirably flowed in contact with the ion exchanger to increase the amount of the monovalent ion form, while a bivalent ion form is so suitable for mutual separation of saccharides having the same molecular weight that an aqueous solution of a salt such as calcium chloride is desirably flowed in contact with the ion exchanger to increase the amount of the bivalent ion form. The process of the present invention is preferably carried out under such conditions that the ionic form composition of the ion exchanger is not substantially varied in keeping with the progress of separation operation in order to maintain the resolution constant. For example, in separation of saccharides with use of an ion exchange resin, however, either a case where the ionic form thereof goes in such a direction as to approach the ionic form composition equilibrated with various kinds of ions contained in a starting solution material or a case where some ions of the ion exchange resin in a certain packing bed (e.g., a packed column unit) move to a next packing bed may arise in keeping with progress of operation. Even in such a case, however, no problems arise in so far as there exists an amount of the ionic forms; A necessary for separation per total amount of the ion exchange resin in the whole packing bed.
A generic and simple description will now be made of an example of the basic simulated moving bed chromatographic separator that can be used in the chromatographic separation process of the present invention. Incidentally, although a case where a liquid containing at least 3 components is dealt with as the starting fluid material will mainly be described in order to simplify the description of the process of the present invention, it goes without saying that the process of the present invention is applicable to gases containing at least 3 components. This separator comprises a system comprising a plurality of packing bed units linked in endless series and packed with solid sorbent (comprising at least ion exchanger in the present invention), a means for circulating internal fluid in one direction in the system, a starting fluid material feed means for choosing any one of the packing bed units and feeding thereto a starting fluid material, a desorbent feed means for choosing any other one of the packing bed units and feeding thereto desorbent (also called xe2x80x9celuentxe2x80x9d in the case of liquid), a first fluid withdrawal means for choosing any one of the packing bed units and withdrawing therefrom a fraction A (e.g., raffinate) out of the system, a second fluid withdrawal means for choosing any other one of the packing bed units and withdrawing therefrom a fraction C (e.g., extract) out of the system, and a switching control means for sequentially displacing the fluid feed positions and the fluid withdrawal positions in the downstream direction of fluid flow in the system while maintaining the relationship between the fluid feed positions and the fluid withdrawal positions in the system.
A generic and simple description will now be made of an example of a simulated moving bed chromatographic separation process using this simulated moving bed chromatographic separator. The group of the packing bed units linked in endless series is regarded as being divided into first, second, third and fourth sections in the downstream direction of fluid flow when viewed from the desorbent feed position. Desorbent such as eluent is fed via a feed valve to circulating fluid at the inlet of a packing bed unit positioned foremost in the first section and the fraction C large in the amount of a sorbed component, such as extract, is withdrawn via a withdrawal valve from circulating fluid at the outlet of a packing bed unit positioned rearmost in the first section, while a starting fluid material is fed via a feed valve to circulating fluid at the inlet of a packing bed unit positioned foremost in the third section and the fraction A small in the amount of the sorbed component, such as raffinate, is withdrawn via a withdrawal valve from circulating fluid at the outlet of a packing bed unit positioned rearmost in the third section. The desorbent feed position, the fraction C withdrawal position, the starting fluid material feed position, and the fraction A withdrawal position are each operationally displaced one by one in the downstream direction in keeping with the movement of a zone wherein the component in the starting fluid material is sorbed on sorbent. According to the present invention, such a simulated moving bed chromatographic separation process is carried out in a plurality of steps in each of which the ionic form of an ion exchanger used in the process is changed, whereby the starting fluid material containing at least 3 components can be separated into at least 3 fractions. However, simulated moving bed chromatographic separation processes include various improved or altered methods, examples of which include a method wherein the starting fluid material feed position is fixed (see Japanese Patent Laid-Open No. 132,586/1997), and a method wherein the position of withdrawing a certain fraction is fixed (see Japanese Patent Laid-Open No. 132,586/1997).